Layered sustained-release microbeads and methods of making the same

ABSTRACT

A layered microbead suitable for incorporating into a non-prescription consumable product is disclosed. The layered microbead may include a core and at least one active ingredient layer encapsulating the core. The active ingredient in the core can be different from the active ingredient in the encapsulating layer. The active ingredient in the core can be selected to counteract or enhance the effect of the active ingredient in the encapsulating layer. The layered microbead can further incorporate microspheres of active ingredient surrounded by polymer material. Method of manufacturing microspheres and microbeads are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS INCORPORATED BY REFERENCE

This application is a continuation of U.S. patent application Ser. No.14/732,574 filed Jun. 5, 2015, now issued as U.S. Pat. No. 9,931,344,which claims priority to and the benefit of U.S. Provisional PatentApplication No. 62/102,477 filed Jan. 12, 2015, and U.S. ProvisionalPatent Application No. 62/150,181 filed Apr. 20, 2015. The foregoingapplications are incorporated herein by reference in their entirety. Tothe extent the foregoing applications or any other material incorporatedherein by reference conflicts with the present disclosure, the presentdisclosure controls.

BACKGROUND

Individuals taking supplements and/or medications are often required toingest capsules, pills, tablets, or the like, multiple times per week,and in some instances, multiple times per day, in order to receive thenecessary amount of active ingredients contained therein at theappropriate time. Traditionally, this requires individuals toself-monitor their supplement/medicine in-take, as through the use of amedication log or pill box having multiple labeled compartments. Thesemethods provide ample opportunity for human error. Additionally, therequirement of having to take multiple pills per day or per week can becumbersome and inconvenient. Further still, many individuals havedifficulty taking medicine or supplements in the form of capsules,pills, tablets, and the like, due to their difficulty in swallowing suchitems.

To solve some of these problems, medications and/or supplements havebeen provided in sustained-release tablets, pills, or capsules.Sustained-release tablets, pills, or capsules attempt to alleviate theburdens of taking numerous pills, tablets or capsules per day byproviding relatively large amounts of medicine in a single pill thatgradually releases the active ingredient over an extended period of timeonce ingested. However, shortcomings of these sustained-release pills,capsules, or tablets can include a limited time period during whichactive ingredients are released (e.g., over 8 hours or less), a largesize that is difficult to swallow, the delivery of only a single type ofactive ingredient, and the inability to provide finer tuned delivery ofnumerous active ingredients, including, e.g., desired time gaps betweenthe delivery of active ingredients.

SUMMARY

This Summary is provided to introduce a selection of concepts insimplified form that are further described below in the DetailedDescription. This Summary, and the foregoing background, is not intendedto identify key aspects or essential aspects of the claimed subjectmatter. Moreover, this Summary is not intended for use as an aid indetermining the scope of the claimed subject matter.

In some embodiments, a layered microbead is disclosed. The layeredmicrobead can include a core and at least one active ingredient layerencapsulating the core. The core can include a plurality of microspheresintimately mixed together with binding agent such that binding agent andmicrospheres are located throughout the core. The microspheres caninclude at least one active ingredient and a polymer materialencapsulating the at least one active ingredient. The at least oneactive ingredient layer can include at least one active ingredient and abinding agent. In some embodiments, the active ingredient in themicrospheres is a different active ingredient from the active ingredientincluded in the active ingredient layer. In some embodiments, the activeingredient in the core is one which either counters or enhances theeffects of the active ingredient in the active ingredient layer. In someembodiments, the layered microbead is a non-prescription microbead.

In some embodiments, a non-prescription consumable product is disclosed.The consumable product may have incorporated therein a layeredmicrobead. The layered microbead may include a core and an activeingredient layer encapsulating the core. An active ingredient may bepresent in both the core and the active ingredient layer. In someembodiments, the active ingredient in the core is a different activeingredient from the active ingredient in the active ingredient layer. Insome embodiments, the active ingredient in the core is one which eithercounters or enhances the effects of the active ingredient in the activeingredient layer.

In some embodiments, a method of manufacturing a layered microbead isdisclosed. The method can include a step of mixing at least one activeingredient with at least one polymer to form a mass. The method canfurther include a step of micronizing the mass to form microspheres. Themicrospheres may be active ingredient encapsulated by the polymer. Themethod can further include a step of forming a microbead core and/or amicrobead active ingredient layer incorporating the microspheres.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting and non-exhaustive embodiments of the methods and systemsdisclosed herein are described with reference to the following Figures,wherein like reference numerals refer to like parts throughout thevarious views unless otherwise specified.

FIG. 1 is a cross sectional diagrammatic view of a layered microbeadaccording to various embodiments described herein;

FIG. 1A is a cross sectional diagrammatic view of another layeredmicrobead according to various embodiments described herein;

FIG. 1B is a cross sectional diagrammatic view of yet another layeredmicrobead according to various embodiments described herein;

FIG. 1C is a cross sectional diagrammatic view of yet another layeredmicrobead according to various embodiments described herein;

FIG. 1D is a cross sectional diagrammatic view of yet another layeredmicrobead according to various embodiments described herein;

FIG. 2 is a flow diagram illustrating a method of forming layeredmicrobeads according to various embodiments described herein;

FIG. 3 is a simplified cross sectional illustration of an encapsulatordevice suitable for use in a co-extrusion process according to variousembodiments described herein; and

FIG. 4 is a flow diagram illustrating a method of forming layeredmicrobeads according to various embodiments described herein.

DETAILED DESCRIPTION

With reference to FIG. 1, a layered microbead 100 according to variousembodiments described herein includes a microbead core 110 and at leastone active ingredient layer 120 encapsulating the microbead core 110. Atleast one active ingredient is generally present in each of themicrobead core 110 and the at least one active ingredient layer 120.

The microbead 100 is generally designed such that, once ingested by aconsumer, the active ingredient in the active ingredient layer 120 ispartially or fully released into the GI tract of the consumer prior tothe release of the active ingredient in the microbead core 110. In thismanner, the disclosed microbead is capable of providing both sustainedand sequential release of active ingredients to a consumer.

The microbead 100 is generally spherical in shape, although other shapescan also be provided. In some embodiments, the diameter of the microbead100 is in the range of from 1 to 5000 microns. The microbeads 100 aredesigned to be in this range such that the presence of the microbeads isgenerally masked when a consumer ingests the microbeads, including whenthe microbeads are incorporated into a food or drinkable consumerbeverage product.

Generally speaking, the microbeads described herein are considered to bedifferent from a capsule or tablet for several reasons. For example, thesize of microbeads are smaller than tablets and capsules, making themgenerally easier to ingest. In some embodiments, the microbeadsdescribed herein have a size in the range of from 1 to 5,000 microns,while tablets and capsules are significantly bigger (e.g., 5,000 to10,000 microns). Because microbeads are smaller than tablets andcapsules, it becomes easier to incorporate multiple microbeads,including micobeads having different active ingredients, into a singleconsumable product, such as a food or beverage product. In contrast,large capsules and tablets are difficult to incorporate into a food orbeverage.

The microbead core 110 can generally have a spherical shape and servesas the innermost portion of the microbead 100. The size of the microbeadcore 110 is generally not limited, though in some embodiments, themicrobead core 110 has a diameter in the range of from 1 to 5,000microns. The size of the microbead core 110 is generally kept relativelysmall such that the overall size of the microbead 100 is minimized. Amicrobead 100 having a relatively small size is generally desired suchthat the microbeads 100 can be incorporated into a food or drinkableconsumer beverage and be consumed by a consumer without the consumergenerally feeling the microbeads during ingestion.

In some embodiments, the microbead core 110 includes one or more activeingredients. In some embodiments, the microbead core 110 is made ofexclusively active ingredients, while in other embodiments, themicrobead core 110 can include active ingredients and other components.In one example, the microbead core 110 can include one or more activeingredients and one or more binding agents. The active ingredients, andbinding agents can be intimately mixed so that both components arepresent throughout the core 110.

The binding agents can be used to help maintain the shape and stabilityof the microbead core 110 and/or control the rate at which the microbeadcore 110 breaks down once the microbead core 110 is exposed to the GItract of the consumer. Any binding agent capable of providing stabilityto the microbead core 110 can be used and any combination of bindingagents can be used. Exemplary binding agents suitable for use in themicrobead core 110 include, but are not limited to methyl cellulose,ethyl cellulose, microcrystalline cellulose, croscarmellose sodium,dicalcium phosphate, cellulose, hypromellose, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose,povidone, polylactic acid, hypromellose, lipids/waxes, trigylcerides,phospholipids, carnuba wax, cottonseed oil, palm oil, soybean oil, andstearines.

In some embodiments, the microbead core can further include one or moreion exchange resins. Ion exchange resins can provide stability to themicrobead core by altering characteristics of the active ingredient in amanner that makes the active ingredient better suited for incorporationinto the core. In some embodiments, the ion exchange resin is used tochange the polarity, charge level, and/or solubility of the activeingredient to thereby stabilize the active ingredient in the core. Anysuitable ion exchange resins can be used in any combination. Exemplaryion exchange resins include, but are not limited, AmberlitePharmaceutical Grade Cation and Anion Exchange resins manufactured byRohm-Haas.

In some embodiments, the microbead core can further include one or morecomplexing agents. Complexing resins and agents can provide stability tothe microbead core by altering characteristics of the active ingredientin a manner that makes the active ingredient better suited forincorporation into the core. In some embodiments, the complexing agentis used to change the polarity, charge level, and/or solubility of theactive ingredient to thereby stabilize the active ingredient in thecore. Any suitable complexing agents can be used in any combination.Exemplary complexing agents include, but are not limited to,cyclodextrins, sodium chloride, potassium chloride, magnesium chloride,and calcium chloride, tannins, monocarboxylic acid, dicarboxylic acid,multi-carboxylic acid, 1-hydroxy 2-naphthoic acid, adipic acid, benzoicacid derivatives, caffeic acid, ellagic acid, ethyl gallate acid,gestistic acid, glutamic acid, glutaric acid, maleic acid, malonic acid,oxalic acid, succinic acid, and combinations thereof.

In some embodiments, the microbead core can further include one or morepolymers. Polymers can provide stability to the microbead core byaltering characteristics of the active ingredient in a manner that makesthe active ingredient better suited for incorporation into the core. Insome embodiments, the polymer is used to change the polarity, chargelevel, and/or solubility of the active ingredient to thereby stabilizethe active ingredient in the core. Any suitable polymers can be used inany combination. Exemplary polymers include, but are not limited to,methyl cellulose, ethyl cellulose, microcrystalline cellulose,croscarmellose sodium, dicalcium phosphate, cellulose, prolamine protein(Zein), hypromellose, polylactic acid, hydroxypropyl methylcellulose,carboxymethylcellulose, hydroxyethyl cellulose, povidone, hypromellose,lipids/waxes, trigylcerides, phospholipids, carnuba wax, cottonseed oil,palm oil, soybean oil, and stearines.

In some embodiments, the microbead core can further include one or morecarrier agents. Carrier agents can provide stability and flowability inthe manufacturing process and to the final microbead core by alteringcharacteristics of the active ingredient in a manner that makes theactive ingredient better suited for incorporation into the core. In someembodiments, the carrier agent is used to change the polarity, chargelevel, and/or solubility of the active ingredient to thereby stabilizethe active ingredient in the core. Any suitable carrier agents can beused in any combination. Exemplary carrier agents include, but are notlimited to, water, propylene glycol, Dibutyl sebacate, sunflower oil,oleic oil, corn oil, palm oil, coconut oil, palm kernel oil, rapeseedoil, cocoanut butter oil, soybean, cottonseed, omega oil, olive oil,carnuba palm oil, migloyl oil, vegetable oil, and hydrogenated versionsof listed oils.

When a microbead core 110 includes both active ingredients and bindingagent, the microbead core 110 can include from 5 to 95 wt % activeingredient and from 5 to 95 wt % binding agent (based on the totalweight of the microbead core). In some embodiments, the 5 to 95 wt %binding agent includes the ion exchange resins, complexing agents,and/or polymers used in the cores.

Other components can also be included in the microbead core 110 toprovide additional desired effects. Additional components that may beincluded in the microbead core 110 include, but are not limited to, pHbalancers, fillers, and excipients. These components can be present inthe microbead core 110 in any amount necessary to provide the desiredeffect.

The active ingredient layer 120 generally encapsulates the microbeadcore 110 such that the microbead core 110 can only be accessed bybreaching the active ingredient layer 120. As shown in FIG. 1, theactive ingredient layer 120 can have a uniform thickness, though activeingredient layers having non-uniform thickness are also possible. Thethickness of the active ingredient layer 120 is generally not limitedand can be varied based on a variety of different factors, including,for example, the amount of active ingredient to be provided in theactive ingredient layer and the rate at which the active ingredientlayer is desired to break down. In some embodiments, the activeingredient layer 120 has a thickness in the range of 10 to 2,500microns.

The active ingredient layer 120 generally includes one or more activeingredients. In some embodiments, the active ingredient layer 120 ismade of exclusively active ingredients, while in other embodiments, theactive ingredient layer 120 can include active ingredients and othercomponents. In one example, the active ingredient layer 120 can includeone or more active ingredients and one or more binding agents. Theactive ingredient and binding agent can be intimately mixed so that bothcomponents are present throughout the core 110.

The binding agents can be used to help maintain the shape and stabilityof the active ingredient layer 120. The binding agent can also beprovided to vary the rate at which the active ingredient layer 120breaks down once ingested by a consumer. Any binding agent capable ofproviding stability to the active ingredient layer 120 can be used andany combination of binding agents can be used. Exemplary binding agentssuitable for use in the active ingredient layer 120 include, but are notlimited to methyl cellulose, ethyl cellulose, microcrystallinecellulose, croscarmellose sodium, dicalcium phosphate, cellulose,hypromellose, hydroxypropyl methylcellulose, carboxymethylcellulose,hydroxyethyl cellulose, povidone, hypromellose, lipids/waxes,trigylcerides, phospholipids, carnuba wax, cottonseed oil, palm oil,soybean oil, and stearines.

When an active ingredient layer 120 includes both active ingredients andbinding agent, the active ingredient layer 120 can include from 5 to 95wt % active ingredient and from 5 to 95 wt % binding agent (based on thetotal weight of the active ingredient layer). In some embodiments, the 5to 95 wt % binding agent further includes ion exchange resins and/orcomplexing agents.

In some embodiments, the presence of binding agents in the activeingredient layer 120 helps to prevent the substantial breakdown of themicrobeads prior to ingestion by a consumer, such as when the microbeadsare incorporated into a food or drinkable consumer beverage product andhoused in the food or drinkable consumer beverage product for a periodof time. Accordingly, in some embodiments, the amount of binding agentincluded in the active ingredient layer is specifically selected toprevent the substantial breakdown of the microbeads in theseenvironments.

The ion exchange resins, complexing agents, carrier agents, and/orpolymers discussed above with respect to the microbead cores 110 canalso be used in any combination in the active ingredient layer 120. Asdiscussed in greater detail above, the ion exchange resin, complexingagents, carrier agents, and/or polymers can be used to, e.g., altercharacteristics of the active ingredient component of the activeingredient layer and thereby stabilize the active ingredient layer.

Other components can also be included in the active ingredient layer 120to provide additional desired effects, such as providing additionaldefense against the substantial breakdown of microbeads incorporatedinto a food or drinkable consumer beverage product. Additionalcomponents that may be included in the active ingredient layer 120include, but are not limited to pH balancers, fillers, and excipients.These components can be present in the active ingredient layer 120 inany amount necessary to provide the desired effect.

With reference to FIG. 1A, the disclosed layered microbead 100A canfurther include one or more exterior sealing layers 130. A sealing layercan generally be provided to ensure the layered microbead 100A can bestored for a period of time in a food or drinkable consumer beveragewithout the microbead substantially breaking down in the food ordrinkable consumer beverage. Accordingly, the sealing layer 130 ispreferably made from a material or combination of materials that willnot substantially break down in a food or drinkable consumer beverageproduct but which will substantially break down in a consumer's GItract. As used herein, the term substantially breakdown means that themicrobead or component of the microbead fully deteriorates at a rate ofless than 24 hours and, in some cases, in less than 8 hours. When themicrobead or component of the microbead is designed to not substantiallybreak down, this means that the microbead or component of the microbeaddoes not fully deteriorate for at least a period of 24 hours and, insome cases for at least a period of days, weeks, months, or years. Forexample, when the microbeads are incorporated into a food or drinkableconsumer beverage product that will then be sold to consumers at retailsstores, it is necessary for the microbeads to not substantially breakdown for a sufficient period that provides the food or drinkableconsumer beverage product with the necessary shelf life. In someembodiments, this shelf life needs to be several days, a week or more, amonth or more, or more than 1 year. As a result, the microbeads andcomponents of the microbeads should be capable of not substantiallybreaking down during the appropriate shelf life period.

In some embodiments, the sealing layer includes binding agents similaror identical to those optionally used in the microbead core and/oractive ingredient layer. Exemplary components suitable for use in thesealing layer 130 include, but are not limited to alginate derivatives,trehalose (mylose), hydroxyectoine, o-toluidine, maltitol, lactitol,pamatinit, ectoine, polystyrene, polyvinylchloride, polycarbonate,polylactic acid polyethylene, mylar, cellophane, polyacrylates,ethylene-vinyl acetate polymers, non-erodible polyurethanes, polyvinylfluoride, polyvinyl imidazole, chlorosulphonated polyolifns,polyethyleneoxide, polyvinyl alcohol, nylon, poly lactide, poly glycolicacid (PGA), polylactide-co-glycolide (PLGA), polycarbonates,Polycaprolactone, Polyamides, Polyanhydrides, Polyamino Acids,Polyorthoesters, Polyacetals, Polyhydroxyalkanoates, Polycyanoacrylates,Degradeable Polyurethanes, gums, latex, rubber, Cellulose AcetatePhthalate (Eastman-Cellacephate CAP), Vinyl Acetate Crotonic AcidCopolymer (Luviset), Methacrylic Acid/(Meth) Acrylic Acid EsterCopolymer (Eudragit), Hydroxypropyl Methylcellulose Phthalate,Polystyrene-Poly(Methylacrylate), Fillers/Plasticizers (such as CaCO3,Talc, TiO2, PEG, PVP), lipids and waxes, cottonseed, carnuba, olieic,soybean, palm, oleic, coconut, and hydrogenated versions of the listedabove lipids and waxes, whey proteins, and combinations thereof.

The sealing layer 130 will generally encapsulate the microbead 100 suchthat the active ingredient layer 120 and the microbead core 110 cannotbe accessed without breaching the sealing layer 130. As shown in FIG.1A, the sealing layer 130 has a uniform thickness, although embodimentswhere the sealing layer has a non-uniform thickness are also envisioned.The sealing layer 130 can have any suitable thickness, and the specificthickness selected will often depend on the food or drinkable consumerbeverage in which the microbeads may be deposited. For example, in foodor drinkable consumer beverages having the ability to more quickly breakdown the sealing layer (e.g., acidic foods or drinkable consumerbeverages), the thickness may be larger to prolong shelf life. In foodor drinkable consumer beverages less capable of breaking down thesealing layer, the thickness may be smaller while still providing thedesired shelf life. In some embodiments, the sealing layer has athickness in the range of from 10 to 2,500 microns.

With reference to FIG. 1B, a microbead 100B having multiple activeingredient layers 120 a, 120 b, 120 c is illustrated. While themicrobead 100B shown in FIG. 1B shows a microbead 100B having threeactive ingredient layers 100, any number of active ingredient layers canbe provided.

Each active ingredient layer 120 a, 120 b, 120 c can be similar oridentical to the active ingredient layer 120 described above in FIG. 1.Each active ingredient layer 120 a, 120 b, 120 c can include one or moreactive ingredients and can also optionally include other components suchas binding agents. The active ingredient layers 120 a, 120 b, 120 c canall include the same active ingredients or one or more active ingredientlayer can include different active ingredients from the other activeingredient layers. The active ingredient layers 120 a, 120 b, 120 c, canall have identical thicknesses or one or more active ingredient layercan have a different thickness from the other active ingredient layers.The active ingredient layers 120 a, 120 b, 120 c can all include bindingagent, or only one or some of the active ingredient layers 120 a, 120 b,120 c can have binding agent. When the active ingredient layers 120 a,120 b, 120 c include binding agent, each layer can have an identicalamount of binding agent or one or more active ingredient layer can havea different amount of binding agent from the other active ingredientlayers.

In view of the above described variability possible in the activeingredient layers, the active ingredient layers 120 a, 120 b, 120 c caneach be specifically designed to provide a variety of desired effects.In one example, the amount of binding agent in an outer most activeingredient layer 120 a can be lower than the other layers 120 b, 120 csuch that, upon ingestion of the microbead, active ingredients in thelayer 120 a are quickly released into the GI tract of the consumer,while the active ingredients in the layers 120 b and 120 c are moreslowly released into the GI tract. In another example, the amount ofbinding agent in an outer most active ingredient layer 120 a can behigher than the other layers 120 b, 120 c such that, upon ingestion, theactive ingredients in the layer 120 a are released slowly, while theactive ingredients in the layers 120 b, 120 c are released more quickly.This can provide for a situation where the microbead provides delayedrelease of the active ingredient, but normal continuous release ofactive ingredients once the initial delay is over.

While not shown in FIG. 1B, the microbead 100B can further include asealing layer between some or all of the adjacent active ingredientlayers (in addition to or alternative to the outer sealing layer 130shown in FIG. 1A). The sealing layer provided between adjacent activeingredient layers can be similar or identical to the sealing layer 130described above with respect to FIG. 1A. The presence of additionalsealing layers between adjacent active ingredient layers can help toregulate the rate at which the active ingredients in each activeingredient layer are released into the GI tract of the consumer. Asealing layer located between active ingredient layers will generallyresult in a gap in time between when an active ingredient in an outeractive ingredient layer is released and when an active ingredient in aninner active ingredient layer is released.

In some embodiments, one or more sealing layers are specificallyprovided between the microbead core and the active ingredient layerclosest to the microbead core. Such a sealing layer can be similar oridentical to the sealing layer 130 described above with respect to FIG.1A. The sealing layer between the microbead core and the closest activeingredient layer can help to ensure that there is a period of timebetween the release of the active ingredient in the active ingredientlayer closest to the microbead core and the release of the activeingredient in the microbead core. Such a delay can be useful ininstances where, for example, the active ingredient in the microbeadcore is provided to counteract or reduce the effect of the activeingredients in the active ingredients layer (as will be discussed ingreater detail below).

With reference to FIG. 1C, a microbead 100C can include a core 110 withactive ingredient microspheres 105 distributed throughout the microbeadcore 110. Such a configuration allows for greater design options withrespect to the rate and timing of active ingredient release. Themicrobead spheres 105 can also provide further stability and protectionto the active ingredients located within the microbead spheres 105.

Each microsphere 105 can include one or more active ingredients coatedwith a sealing material. The core of the microspheres 105 can includeexclusively active ingredient or can include other components, such asthe binding agents, complexing agents, ion exchange resins, carrieragents, and/or polymers discussed in greater detail above. The sealingmaterial coated around the active ingredient can fully encapsulate theactive ingredient. In some embodiments, the sealing material of themicrosphere is the polymer material described in greater detail above.In some embodiments, the size of the microspheres is in the range offrom 0.001 to 2000 microns. Methods of forming the microspheres arediscussed in greater detail below.

As shown in FIG. 1C, the microspheres are incorporated into a core 110.The core can be similar or identical to the cores 110 described ingreater detail above. Accordingly, the core can include exclusivelyactive ingredient, or a combination of active ingredient and bindingagent or other components. In still other embodiments, the core materialin which the microspheres 105 are incorporated is free of activeingredient and instead is made from binding agent and/or othercomponents as discussed above. FIG. 1C also shows the core 110 beingsurrounded by an active ingredient layer 120, which is similar oridentical to the active ingredient layer 120 described in greater detailabove.

With reference to FIG. 1D, a microbead 100D is similar to the microbead100C shown in FIG. 1C, with the exception that microspheres 105 are alsoincorporated into active ingredient layer 120. In such embodiments, theactive ingredient layer in which the microspheres 105 are dispersed canalso include active ingredients, or the active ingredient layer 120 canbe free of active ingredient (in which case, the active ingredient wouldbe more similar to the sealing layers described in greater detailabove).

FIG. 1D shows a microbead 100D having a single active ingredient layer120 with microspheres 105 disposed therein. However, the number ofactive ingredient layers 120 is not limited. Similarly, when multipleactive ingredient layers 120 are provided one or more of the activeingredient layers may include microspheres 105, while other activeingredient layers may be free of microspheres 105. The activeingredients included in the various layers, cores, and microspheres canbe the same active ingredient or any combination of different activeingredients.

In any of the embodiments described above, the microbead 100, 100A,100B, 100C, 100D can be substantially or completely free of water. Asused herein, the term substantially free means less than 2.5 wt % waterpresent in the microbead (based on the total weight of the microbead).The absence of water in the microbeads can help to ensure that themicrobeads do not substantially breakdown when incorporated into, e.g.,a drinkable consumer beverage. Instead, the microbeads having little orno water will only begin to appreciably break down upon being exposed tothe GI tract of a consumer.

The active ingredients that can be included in the mircobeads aregenerally not limited and may include any active ingredient thatpromotes or induces any type of effect or change in a human consumer.

Exemplary active ingredients include, but are not limited to,nutraceuticals, vitamins, supplements, minerals, enzymes, probiotics,bronchodilators, anabolic steroids, analeptics, analgesics, proteins,peptides, antibodies, vaccines, anesthetics, antacids, antihelmintics,anti-arrthymics, antibiotics, anticoagulants, anticolonergics,anticonvulsants, antidepressants, antidiabetics, antidiarrheals,anti-emetics, anti-epileptics, antihistamines, antihormones,antihypertensives, anti-inflammatories, antimuscarinics, antimycotics,antineoplastics, anti-obesity drugs, antiprotozoals, antipsychotics,antispasmotics, anti-thrombics, antithyroid drugs, antitussives,antivirals, anxiolytics, astringents, beta-adrenergic receptor blockingdrugs, bile acids, bronchospasmolytic drugs, calcium channel blockers,cardiac glycosides, contraceptives, corticosteriods, diagnostics,digestives, probiotics, diuretics, dopaminergics, electrolytes, emetics,haemostatic drugs, hormones, hormone replacement therapy drugs,hypnotics, hypoglycemic drugs, immunosuppressants, impotence drugs,laxatives, lipid regulators, muscle relaxants, pain relievers,parasympathicolytics, parasympathicomimetics, prostagladins,psychostimulants, sedatives, sex steroids, spasmolytics, sulfonamides,sympathicolytics, sympathicomimetics, sympathomimetics, thyreomimetics,thyreostatic drugs, vasodialators, and xanthines; drugs or medicaments,breath fresheners, vitamins and other dietary supplements, minerals,caffeine, theacrine, cannabis, nicotine, fruit juices, and the like, andmixtures thereof. Examples of useful drugs include ace-inhibitors,antianginal drugs, anti-arrhythmias, anti-asthmatics,anti-cholesterolemics, analgesics, anesthetics, anti-convulsants,anti-depressants, anti-diabetic agents, anti-diarrhea preparations,antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatoryagents, anti-lipid agents, anti-manics, anti-nauseants, anti-strokeagents, anti-thyroid preparations, anti-tumor drugs, anti-viral agents,acne drugs, alkaloids, amino acid preparations, anti-tussives,anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemicand non-systemic anti-infective agents, anti-neoplastics,anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants,biological response modifiers, blood modifiers, bone metabolismregulators, cardiovascular agents, central nervous system stimulates,cholinesterase inhibitors, contraceptives, decongestants, dietarysupplements, dopamine receptor agonists, endometriosis managementagents, enzymes, erectile dysfunction therapies such as sildenafilcitrate, which is currently marketed as Viagra™, fertility agents,gastrointestinal agents, homeopathic remedies, hormones, hypercalcemiaand hypocalcemia management agents, immunomodulators,immunosuppressives, migraine preparations, motion sickness treatments,muscle relaxants, obesity management agents, osteoporosis preparations,oxytocics, parasympatholytics, parasympathomimetics, prostaglandins,psychotherapeutic agents, respiratory agents, sedatives, smokingcessation aids such as bromocryptine or nicotine, sympatholytics, tremorpreparations, urinary tract agents, vasodilators, laxatives, antacids,ion exchange resins, anti-pyretics, appetite suppressants, expectorants,anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances,coronary dilators, cerebral dilators, peripheral vasodilators,psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors,migraine treatments, antibiotics, tranquilizers, anti-psychotics,anti-tumor drugs, anti-coagulants, anti-thrombotic drugs, hypnotics,anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs,hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations,diuretics, anti-spasmodics, terine relaxants, anti-obesity drugs,erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics,DNA and genetic modifying drugs, cannabis, THC, CBD, and combinationsthereof.

The active ingredients selected for use in the consumable can be used toaddress a variety of conditions. In some embodiments, the activeingredients are selected from those generally used to enhance physicalperformance, such as stimulants, electrolytes, vitamins, and minerals.In such embodiments, the consumable matrix can be used to deliver any ofthe active ingredients on demand and in response to a specific event inan athletic competition (e.g., an on demand release of caffeine at thebeginning of a steep climb in a bicycle race). In some embodiments, theactive ingredients can be medicine needed to treat and/or prevent avariety of conditions. In a specific example, the active ingredients areselected to treat life threatening conditions, such as in a human havinga high risk for heart attacks, in which case the consumable can providenitroglycerin on demand (and potentially by a remote user, such as adoctor, monitoring such a patient). In still another embodiment, theactive ingredient can be any type of appetite suppressant such that theconsumable can be used by individuals trying to lose weight. In suchembodiments, the consumable can be used to deliver the appetitesuppressant on demand, such as when the user feels a food craving.

The active ingredients can be included in the microbead in any desiredquantity and in any desired combination. In some embodiments, themicrobeads include two or more active ingredients that are specificallyselected to work in concert to achieve some desired result. Differentactive ingredients can be located in different parts of the microbeadfor sequential release of active ingredients. In some embodiments, afirst active ingredient is included in the one or more active ingredientlayers and a second active ingredient different from the first activeingredient is included in the microbead core. In some embodiments, afirst active ingredient is provided in one or more outer activeingredient layers, and a second active ingredient different from thefirst active ingredient is included in one or more inner activeingredients layers (i.e., active ingredient layers located closer to themicrobead core than the outer active ingredient layers). In suchembodiments, the microbead core can include the first active ingredient,the second active ingredient, a third active ingredient different fromthe first and second active ingredient, or a combination thereof. Amicrobead with multiple active ingredient layers can also includealternating layers of different active layers, such as a microbead witha first, third, and fifth active ingredient layer each including thesame first active ingredient, and a second and fourth active ingredientlayer each including the same second active ingredient that is differentfrom the first active ingredient. Ultimately, and combination of activeingredient layers and active ingredients can be designed to carry outany of a range of desired effects.

In some embodiments, the microbead includes two or more activeingredients, wherein at least one of the active ingredients counteractsor reduces the effect of the one of the other active ingredients.Typically, the active ingredient without the counteracting or reducingeffect will be located in one or more inner active ingredient layersand/or in the microbead core. In this manner, the microbead will releasea first active ingredient from one or more outer active ingredientlayers, followed by the release of a second active ingredient in theinner active ingredient layers and/or microbead core which counteractsor reduces the effect of the first active ingredient.

Any combination of active ingredients where the second active ingredientcounteracts or reduces the effect of the first active ingredient can beused. Exemplary combinations include a sleep aid such as melatonin (toinduce sleep) and a stimulant such as caffeine (to wake up anindividual).

In some embodiments, the microbead includes two or more activeingredients, wherein the at least two active ingredients combine toprovide a complimentary effect or wherein one active ingredient enhancesthe other active ingredient. This can include active ingredients thatare traditionally given separately but in sequential order to obtain adesired effect. Typically, the active ingredient that is to be deliveredfirst will be located in one or more outer active ingredient layers,while the active ingredient that is to be delivered second will belocated in one or more inner active ingredient layers and/or in themicrobead core. In this manner, the microbead will release the firstactive ingredient from one or more outer active ingredient layers,followed by the release of the second active ingredient in the inneractive ingredient layers and/or microbead core which compliments orenhances the effect of the first active ingredient.

Any combination of active ingredients where the second active ingredientenhances or compliments the effect of the first active ingredient can beused.

In some embodiments, the microbeads are specifically formulated so thatthe microbeads are non-prescription and/or not subject to FDAregulation. This can include the use of exclusively non-prescriptionactive ingredients, the use of prescription active ingredients innon-prescription quantities, the use of exclusively GRAS (GenerallyRegarded As Safe) components, the use of exclusively components that areused in GRAS compliant quantities, or combinations thereof. The termGRAS as used herein is intended to include components which arecurrently regarded as GRAS as well as components that may be regarded asGRAS in the future. In some embodiments, the disclosed microbeads aredesigned for over-the-counter sale, including when incorporated intofood and drinkable consumer beverages.

As alluded to above, the microbeads described herein can be incorporatedinto a food or drinkable consumer beverage product such that anindividual consumes a food or drinkable consumer beverage product inorder to consume the microbeads. Any food or drinkable consumer beverageproduct can be used in conjunction with the microbeads. Food productscan include, for example, baked goods, such as bars, breads, cookies,brownies, and the like. Other food products include cereals, oatmeal,yogurts, jellies, and other more fluid-type solids. Drinkable consumerbeverage products can include, for example, water, juices, coffee,shakes, smoothies, energy drinks, sodas, and the like. The microbeadscan also be incorporated into gummies and gels.

When incorporated into food or drinkable consumer beverage products, themicrobeads are typically designed such that the microbeads do notsubstantially breakdown in the food or drinkable consumer beverageproduct for an extended period of time. This allows the products intowhich the microbeads are incorporated to have a sufficient shelf lifeneeded for, for example, retail sale requirements. Any manner ofpreventing the microbeads from substantially breaking down in the foodor drinkable consumer beverage product can be used, including, forexample, providing sealing layers, additional amounts of binding agent,and the like, as discussed in greater detail above.

The microbeads can also be stored and/or sold in stick packets so thatthe microbeads can be added to a food or drinkable consumer beverageproduct at a later time. In one specific example, a stick packet isprovided wherein the amount of microbeads stored therein is a specificquantity making the microbeads suitable for incorporation into astandard water bottle (e.g., a water bottle having 16.9 fluid ounces ofwater). In such embodiments, the microbeads stored in the stick packetsmay require fewer sealing layers or less binding agents since themicrobeads are only added to the food or drinkable consumer beverageproduct upon the consumers intention to ingest the food or drinkableconsumer beverage product.

With reference to FIG. 2, a method 200 of preparing the microbeadsdescribed herein can generally include the following steps: a step 210of forming a microbead core, a step 220 of forming one or more activeingredient layers, such as via powder layering techniques, and anoptional step 230 of forming a sealing layer.

Regarding step 210 of forming a microbead core, this step can includeusing any technique or method known for creating micron-scale, generallyspherical cores that include at least an active ingredient. In someembodiments, the microbead core is formed using rotary granulationtechniques, powder layering techniques, spray drying techniques, spraychilling techniques, liquid extrusion/coextrusion, 3-D Printing.concentric nozzles, extrusion/spheronization, and combinations thereof.

In the rotary granulation technique, a rotary granulator is generallyemployed, and any suitable rotary granulator capable of formingmicron-scale cores can be used. The method of forming the microbead coregenerally includes depositing a dry powder into the rotary granulator,which is then blown airborne. Once airborne, a liquid is sprayed intothe chamber of the rotary granulator. Agglomeration of the microbeadcores occurs via coalescence. The process forms spherical-shaped coresof generally uniform size.

The dry powder mix deposited in the rotary granulator can include atleast the one or more active ingredients to be present in the microbeadcore. The dry powder mix can include other optional components of themicrobead core, as desired, such as the binding agent and othercomponents discussed above. The amount of active ingredients and othercomponents present in the dry powder mix can be similar or identical tothe amounts discussed above.

The liquid sprayed into the rotary granulator can include at least theone or more binding agents to be present in the microbead core. In someembodiments, the rotary granulator produces a core that is an intimatemixture of active ingredient and binding agent (i.e., both the activeingredient and the binding agent are dispersed throughout the core). Theamount of binding agent sprayed into the rotary granulator can be inaccordance with the amounts described above with respect to the make-upof the core.

The size of the microbead cores formed in the rotatory granulator can besimilar or identical to the size ranges discussed above. In someembodiments, the size of the microbead cores is in the range of from 50to 500 microns. In some embodiments, the resulting micobead cores formedin the rotary granulator are dry and substantially free of water.

In the spray drying technique, formation of the microbead cores beginsby preparing a solution or dispersion containing at least the one ormore active ingredients to be included in the microbead core. Thedispersion or solution is then atomized and sprayed into a chamberthrough a heated air stream. This causes the liquid component of thesolution or dispersion to evaporate quickly, resulting in dried,generally spherical shaped microbead cores. The spray drying system mayhave two or three nozzles for the process.

The solution or dispersion can include one or more active ingredient asdiscussed in greater detail above. The dispersion can further includecomponents such as binding agents, fillers, etc, as discussed in greaterdetail above. The amount of active ingredients and other components canbe similar or identical to the amounts discussed above. In someembodiments, the spray drying technique can be used to produce a corethat is only active ingredients. In other embodiments, the coresproduced are intimate mixtures of binding agent, active ingredient, andother optional components.

The size of the microbeads formed by the spray drying technique can besimilar or identical to the size ranges discussed above. In someembodiments, the size of the microbead cores is in the range of from 1to 2000 microns. The microbead cores formed by this method can besubstantially free of water.

In the spray chilling technique, the active ingredient and binding agentare mixed together in a heated pressurized container such that thesystem is brought into a molten state. The liquid resulting from thisstep is then sprayed (e.g., via an atomizer) into a cool stream. Whenthe sprayed liquid contacts the cool stream, the droplets solidify andform particles. No solvent is needed in this process. The cores producedby the chilling technique can be intimate mixtures of active ingredientsand binding agents.

In some embodiments, the microbead cores are formed using anencapsulator device. Exemplary encapsulator devices include, but are notlimited to, the Buchi Encapsulator B-390 manufactured by BuchiLabortechnik AG of Flawil, Switzerland. Encapsulator devices generallyinclude a nozzle through which a microbead core solution is passed toform a stream of droplets of the solution material. The size of thedroplets can be adjusted using, e.g., vibration applied proximate thenozzle and the flow rate of the solution through the nozzle. In someembodiments, the nozzle is vertically oriented such that droplets leavethe nozzle under the force of gravity and collect in a liquid bathpositioned under the nozzle. When the droplets contact the liquid bath,microbead core formation occurs, such as solidification effected viacooling or heating of the droplets. Any suitable liquid bath can be usedto collect the droplets, including, e.g., aqueous solutions containingcations with a 2+ charge (e.g., Ca2+, Cu2+, Fe2+, Sn2+, Cr2+, Mn2+,Mg2+, Zn2+, etc.) and organic solutions that perform a cooling function(e.g., ethanol, methanol, etc.).

Formation of hardened microbead cores can also be assisted by heating orcooling the air through which the stream of droplets travel prior tohitting the liquid bath. The cores formed in the liquid bath may havehydrophobic or hydrophilic characteristics. Once the cores are formed inthe liquid bath, the cores can be collected and subjected to furtherprocessing steps, such as the active ingredient layer coating stepsdiscussed below.

The microbead core solution that is pumped into and through the nozzleof the encapsulator device can generally include the one or more activeingredient to be included in the microbead core and any other materialused to bind together the microbead core (e.g., carrier material,polymers, and binding agents). The amount of each component included inthe solution is generally consistent with the ranges of materialdescribed above for the microbead cores. The different components of themicrobead core solution are generally mixed together prior to beingpumped to the nozzle. In some embodiments, the lines between themicrobead core solution and the nozzle of the encapsulator device areheated lines to ensure that all of the components of the microbead coresolution are suitably liquefied.

In the 3-D printing technique, formation of the microbead cores beginsby preparing a dispersion or filament containing a polymer and/or atleast the one or more active ingredients to be included in the microbeadcore. Multiple dispersions or filaments may be used containing polymersor one or more active ingredients, individually or in combination. Thedispersion or filament is then printed in layers onto the base of the 3Dprinter in the form of a microbead core. The specific size and shape ofthe core can be selected and controlled by using different softwareprograms run on the 3D printer. When the dispersion is a combination ofpolymer and active ingredient, the core formed by the 3D printing methodcan be an intimate mixture of polymer and active ingredient throughoutthe core.

Regarding step 220 of forming one or more active ingredient layers, theactive ingredient layer can be formed by any suitable manner of forminga layer encapsulating the microbead core formed in step 210. Exemplarylayering techniques include, but are not limited to, powder layering and3D printing methods.

When powder layering is used, the powder layering generally includesspraying the one or more components of the active ingredient layer intoa chamber that contains microbead cores. In some embodiments, both anactive ingredient and a binding agent are sprayed into the chamber. Thebinding agent generally serves to saturate the microbead cores andinteract with the active ingredient, which results in the formation of alayer of active ingredient on top of and encapsulating the microbeadcore.

In some embodiments, the powder layering is carried out in a rotarygranulator. The binding agent and active ingredient can each be sprayedinto the chamber using nozzles having a tangent nozzle position. Whencarried out in a rotary granulator, the layers are densified andspheronized via contact with the spinning rotor plate of the rotarygranulator.

The powder layering step can be carried out multiple times, includingwith different active ingredients and/or binding agents, to formmultiple active ingredient layers over the core.

In some embodiments, the layering step 220 is carried out using a 3-Dprinting technique. Formation of the layers begins by preparing adispersion or filament containing a polymer and/or at least the one ormore active ingredients to be included in the active ingredient layer.The dispersion or filament is then layered/printed on, over, and/oraround the core formed in step 210. In some embodiments, a bottomportion of the active ingredient layer can be printed, followed byplacing the core in the bottom portion of the active ingredient layer(e.g., such as by the core in a “nest” that is the bottom portion of theactive ingredient layer), and subsequently printing the remainingportion of the active ingredient layer over, around and/or on top of thecore to encapsulate the core. The printing of the active ingredientlayers is carried out systematically utilizing the 3-D printing systemand software. Multiple layers of active ingredient layers can be formedon a single core by repeating the 3D printing step.

In order to create multiple layers, the layering step 220 can be carriedout multiple times with different and/or identical active ingredientsand binding agents. For example, a first active ingredient layer can beformed on a microbead core according to any of the methods discussedabove, followed by adding additional layers by any of the methodsdiscussed above. In some embodiments where powder layering is used, themicrobead cores formed in step 210 are coated with an active ingredientlayer via powder layering in a rotary granulator. The layered microbeadcore is then left in the chamber. The active ingredient being sprayedinto the chamber is then changed and the process is repeated, with thebinding agent saturating the layered microbead and interacting with thesecond active ingredient to thereby form a second active ingredientlayer. This process can be carried out any number of times with anynumber of active ingredients, including the use of identical activeingredients for multiple active ingredient layers.

Regarding optional step 230, a sealing layer (or sealing layers) can beformed on the microbead. In some embodiments, the sealing layer isformed as the outermost layer of the microbead. In some embodiments, themicrobead includes multiple sealing layers, with some sealing layersbeing between adjacent active ingredient layers and/or between themicrobead core and the inner-most active ingredient layer. These sealinglayers generally serve to slow the release of active ingredients bypreventing access to the layers containing the active ingredients. Asdiscussed above, the outer most sealing layer can serve as a way ofpreventing the microbead from substantially breaking down prior to beconsumed by an individual.

The sealing layer (or sealing layers) formed in step 230 can be similaror identical to the sealing layers discussed in greater detail above.Generally, the sealing layers formed in step 230 do not contain anyactive ingredients. Any manner of forming a sealing layer can be used.In some embodiments, the sealing layer is formed as part of a powderlayering process. 3-D Printing techniques as discussed herein can alsobe used.

In some embodiments, a sealing layer can be formed on top of an activeingredient layer by continuing to spray binding agent into the chamberafter spraying of active ingredient is stopped. The binding agent thatis sprayed into the chamber without also spraying active ingredient intothe chamber saturates the active ingredient layer and begins toaccumulate on the surface of the microbead to thereby form a sealinglayer that includes only binding agent. This process can be used to formsealing layers throughout the microbead.

In some embodiments, steps 210 and 220 can be performed simultaneously.For example, coextrusion and 3D printing methods can both be used toeffectively carry out the formation of the microbead core and one ormore surrounding layers at the same time.

With reference to FIG. 3, the coextrusion method can generally includethe use of an encapsulator device 300 as described above, but whereinthe encapsulator device 300 is fitted with a concentric nozzle 310. Theconcentric nozzle 310 includes an inner passage 310 a and an outerpassage 310 b aligned concentrically with the inner passage 310 a.Material for the microbead core can be pumped through the inner passage310 a, while material for the encapsulating active ingredient layer canbe pumped through the outer passage 310 b. The terminal ends of theinner passage 310 a and the outer passage 310 b are aligned so that whenmaterial exits out of each passage, the active ingredient layer materialencapsulates the microbead core material and forms a stream of layereddroplets 330. As described previously, this stream of droplets 330 fallsunder the force of gravity into a liquid bath (not shown) which servesto collect the droplets 330 and harden the droplets 300 so that layeredbeads are formed.

The solution for the core can be similar or identical to the solutiondescribed above with respect to step 220 of method 200. For thecoextrusion process, a solution of active ingredient layer is alsoprovided and pumped to the nozzle. The solution for the activeingredient layer generally includes the one or more active ingredient tobe included in the active ingredient layer and any other material usedto in the active ingredient layer (e.g., polymers, lipids, waxes,proteins, gums, and/or binding agents). The amount of each componentincluded in the solution is generally consistent with the ranges ofmaterial described above for the active ingredient layers. The activeingredient layer solution can be The shell material may be at ambienttemperature or heated to temperatures adequate to liquefy thecomponents. The shell material may have hydrophobic or hydrophiliccharacteristics.

Features of the encapsulator device 310 can generally be similar oridentical to the encapsulator device and methods described above withrespect to step 220 of method 200. For example, the encapsulator devicecan be a Buchi Encapsulator B-390 and can include heated lines to ensurethe solution material being pumped to the nozzle is sufficientlyliquidized. Vibration and flow rates can also be adjusted to adjust thesize of the droplets.

While FIG. 3 illustrates an embodiment wherein the nozzle include aninner passage 310 a and a single outer passage 310 b, the nozzle caninclude additional concentrically aligned outer passages to provideadditional layers to the bead, including additional active ingredientlayers or sealing layers.

As with the encapsulator device described previously, the stream oflayered droplets travel through air and are captured in a liquid basin.The air that the layered droplets travel through post-extrusion may bewarmed or cooled (via, e.g., heat exchanger 320 shown in FIG. 3) toaccelerate the formation/hardening process. The liquid in the liquidbasin may include a hydrophilic based-polymer or organic system (i.e.,2+ ion systems, ethanol, methanol, etc). The liquid basin may be heatedor cooled to accelerate the hardening process in the liquid.

3D printing techniques can also be used to carry out the simultaneousformation of the microbead core and one or more active ingredient layersand/or sealing layers. Such a method would generally entail the use of a3D printer having multiple nozzles, with each nozzle depositing adifferent dispersion or filament. As discussed previously, thedispersion or filament can include any combination of ingredients neededfor the micorbead core, the active ingredient layer, or the sealinglayer. The 3D printer with multiple nozzles (running specific softwaredesigned for the specific printing of the microbead) is used to form amicrobead having at least one active ingredient layer or sealing layerin a normal fashion, such as by a sequential layer on top of layerprocess. The specific size and shape of the layered microbead, includingthe size and shape of the core and the thickness of each layerencapsulating the core can be selected and controlled by using differentsoftware programs run on the 3D printer.

Still another optional step that can be included in the above-describedmethod is the incorporation of the formed micro-beads into a food ordrinkable consumer beverage product. The food or drinkable consumerbeverage product is generally a non-pharmaceutical product. The food ordrinkable consumer beverage product can also be a GRAS-compliantproduct.

Any manner of incorporating the micro-beads into a food or drinkableconsumer beverage product is generally not limited. With respect todrinkable consumer beverage products (or viscous food products orgenerally drinkable food or drinkable consumer beverage products), themicrobeads can generally be added to the finished drinkable consumerbeverage product and optionally mixed in order to distribute themicrobeads throughout the drinkable consumer beverage product. Asdiscussed above, the microbeads are generally formulated such that theywill not substantially break down in the drinkable consumer beverageproduct for a period of time. In this manner, the microbeads can beadded to drinkable consumer beverage products during the normalmanufacturing process and then distributed to retailers with themicrobeads incorporated therein. Alternatively, the microbeads can beadded to the drinkable consumer beverage product closer to the actualtime of consumption, such as when a consumer adds the microbeads to adrinkable consumer beverage product just prior to consumption. In suchembodiments, the microbeads can be provided in, for example, individualpackets for easy storage and transport by the consumer.

With respect to food products having a generally solid consistency, themicobeads can be incorporated into the food products in any suitablemanner. In some embodiments, the microbeads can be incorporated into thefood product during the cooking, baking or general preparation of thefood product. For example, when the food product is prepared by firstpreparing a batter or the like, the microbeads can be mixed in with thebatter such that the microbeads are present in the product at the timethe product if cooked, baked, or the like. In such embodiments, themicrobeads can be formulated so as to resist higher cooking or bakingtemperatures without substantially breaking down. Microbeads can also beincorporated into a food product after a cooking or baking step.

With reference to FIG. 4, another method 400 that can be used in thepreparation of a microbead core and/or one or more of the activeingredient layers is illustrated. The method generally includes a step410 of mixing an active ingredient with a polymer to create an activeingredient mass, a step 420 of micronizing the active ingredient mass toform microspheres, and a step 430 of forming a core or an activeingredient layer having the microspheres incorporated therein.

In step 410, one or more active ingredients that are to be a part of themicrobead are mixed with a polymer material to form a mass of polymermaterial having the active ingredient(s) dispersed therein. Any mannerof mixing the active ingredient(s) and the polymer material can be used,provided that the active ingredient is dispersed throughout the polymermaterial.

In some embodiments, the amount of active ingredient in the mass is from5% to 90% (based on the total weight of the active ingredient mass). Insome embodiments, the amount of polymer in the mass is 10% to 95% (basedon the total weight of the active ingredient mass). These ranges help toensure that the active ingredient is present throughout the mass whilealso ensuring that the polymer material is covering the activeingredient material.

The active ingredients used in the forming the active ingredient masscan be any of the active ingredients listed above, including anycombination of the above-listed active ingredients or classes of activeingredients. The polymers can be selected from the group includingmethyl cellulose, ethyl cellulose, microcrystalline cellulose,croscarmellose sodium, dicalcium phosphate, cellulose, hypromellose,hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, povidone, hypromellose, lipids/waxes, trigylcerides,phospholipids, carnuba wax, cottonseed oil, palm oil, soybean oil, andstearines.

Once the mass is prepared, it can generally be treated such that themass is hardened. Any manner of hardening or solidifying the mass can beused. Exemplary methods include fluid bed drying, 3-D Printing,hardening solution bath, spray drying, and spray chilling.

In step 420, the solid mass is micronized to form microspheres. Anymanner of micronizing the mass to form microspheres can be used.Similarly, any suitable apparatus for micronizing the mass can be used.In some embodiments, various parameters of the micronizing step can bealtered to form microspheres of difference size and shape. Generallyspeaking, the microspheres formed have a diameter in the range of from0.5 to 50 microns. Each microsphere formed from the micronizinggenerally includes a sphere of polymer material having activeingredient(s) dispersed throughout the polymer material. In someembodiments, the active ingredients in the microspheres are effectivelycoated by the polymer, which thereby creates a barrier that needs to bebreached in order to access the active ingredient. In this manner, themicrospheres can be used to further alter the sustained release natureof the microbeads into which the microspheres are incorporated.

In step 430, the microspheres can be incorporated into a microbead core,one or more active ingredient layers, or any combination thereof. Themicrospheres can be incorporated into the core by adding themicrospheres with the active ingredient, binding agent, or othercombination of ingredients used to form the core. Similarly, themicrospheres can be incorporated into an active ingredient layer byadding the microspheres with the various components used in forming anactive ingredient layer as described in greater detail above.

In some embodiments, the microspheres can be used in place of the activeingredients components discussed above with respect to the core andactive ingredient layers. In such embodiments, the only activeingredient present in the core and/or active ingredient layers is theactive ingredients present within the microspheres. Alternatively, themicrospheres can be used in conjunction with active ingredient presentin the cores or active ingredient layers.

EXAMPLES Example 1 Rotary Granulation to Form Caffeine Core Bound withHPMC

A dry blend was prepared according to the following table:

TABLE 1 Dosage % Dose Batch Ingredient Grade/Type Wt. (mg) Wt. Wt. (g)Caffeine Anhydrous 99% 70 25 750 Microcrystalline Avicel PH 101 126 451350 Cellulose Hydroxypropyl E5 42 15 450 Methylcellulose SodiumChloride Powdered 42 15 450 Total 280 100 3000

The mixture was deposited in a rotary granulator (model: Freund VectorVCF 3 with a GXR Insert) and air was applied into the chamber of therotary granulator to blend the mixture and cause the mixture to becomeairborne. An interior temperature of 28° C. was achieved. The air wassupplied at 90 psi and 12 cfm.

Water was subsequently sprayed into the rotary granulator using avariable speed peristaltic pump. The nozzle position for the sprayedwater was tangential. The selected rotor disc had a smooth surface.

The overall process was carried out at the following parameters

TABLE 2 Process Time minutes 0 15 30 45 60 75 90 Drying Airflow cfm — —— 50 50 50 50 Slit Air cfm 10 10 10 10 10 10 10 Drying Accel Temp C. — —— 95 95 95 95 Product Temp C. 28 28 28 30 34 42 55 Slit Air Temp C. 5050 50 50 50 50 50 Exhaust Temp C. 30 30 30 32 35 45 57 Rotor Speed rpm400  400  400  400  400  400  400  Spray Rate g/min 40 40 40 — — — —Nozzle Pressure psi 10 10 10 — — — —

Agglomeration of the material (and therefore core formation) beganshortly after introduction of the water. The water began to saturate theairborne powder mix and interacting with the HPMC particles. While thecores grew, they also densified and spheronized via contact with thespinning rotor plate.

Once all of the water was consumed, drying air was activated for anadditional 45 minutes until a product temperature of approximately 55°C. was achieved and dry microbead cores were formed.

Example 2 Spray Drying to Form Caffeine Cores

A solution was prepared according to the following table:

TABLE 3 Dosage % Dose Batch Ingredient Grade/Type Wt. (mg) Wt. Wt. (g)Caffeine Anhydrous 99% 85 85 425 Hydroxypropyl E5 15 15 75Methylcellulose 100 100 500

The solution was mixed using a variable speed mixer and a three-headedpropeller in a suitable container. The solution was mixed until no solidparticulates were observed.

The solution was subsequently sprayed into a spray dryer under thefollowing parameters:

TABLE 4 Spray Rate g/min Inlet Temp C. Outlet Temp C. Spray Conc % 30160 80 10-40

Dried spherical microbead cores were produced having a particle size inthe range of from 1 to 100 microns.

Example 3 Powder Layering Microbead Cores with Caffeine ActiveIngredient Layer

Microbead cores were formed according to the method set forth in Example1.

A binding solution containing 150 g of hydroxylpropyl methylcellulose(E5) was prepared.

The microbead cores from Example 1 were placed in the rotary granulatorof Example 1 equipped with a powder layering nozzle attachment. Bothnozzles positions were tangential.

The binding solution was sprayed through one nozzle concurrently with540 g of caffeine sprayed through the second nozzle under the followingparameters:

TABLE 5 Process Time minutes 0 15 30 45 60 75 90 105 120 135 DryingAirflow cfm — — — — — — — 50 50 50 Slit Air cfm 10 10 10 10 10 10 10 1010 10 Drying Accel Temp C. — — — — — — — 95 95 95 Product Temp C. 27 2727 27 27 27 27 27 32 50 Slit Air Temp C. 50 50 50 50 50 50 50 50 50 50Exhaust Temp C. 31 31 31 31 31 31 31 31 35 54 Rotor Speed rpm 300  300 300  300  300  300  300  300  300  300  Spray Rate g/min 10 10 10 10 2424 24 — — — Nozzle Pressure psi 10 10 10 10 10 10 10 — — — Powder Feedg/min 10 10 10 10 10 — — — — — Eductor Air 14 14 14 14 14 — — — — —

Layering began shortly after the start of the spraying. Once the bindingsolution started to saturate the rotating microbead cores andinteracting with the caffeine powder, growth of the active ingredientlayer on the core began.

Once all of the caffeine powder was consumed, the binding solutionbecame a functional coating, essentially sealing the layered microbeads.

Once all of the binding solution was consumed, drying air was activatedfor an additional 30 minutes until a product temperature of about 50° C.was achieved to dry the microbeads.

Example 4 Microbead Core-Encapsulating Layer Co-Extrusion Process

A microbead core solution was prepared using a carrier agent ofsunflower oil combined with a pre-complexed active component of caffeicacid and caffeine. An encapsulating layer solution was prepared byheating carnuba palm wax to 95° C. The two solutions were then combinedutilizing co-extrusion on a customized Buchi Encapsulator B-390 tomanufacture microbeads having a core and an encapsulating layer. Themicrobeads were collected and allowed to cool in a collection bathreservoir of chilled ethanol. The encapsulation solution is comprised ofthe carnuba palm wax with the ethanol allowing for rapid cooling andhardening of the microbeads.

The overall process was carried out at the following parameters:

TABLE 6 Nozzle System Two Nozzle-Encapsulating Layer 300 μm, Core 200 μmFlow Rate 6 (Encapsulating Layer), 2 (Core) Frequency 600 Hz Pressure0.5 Bar Amp 3 Charge >2000 V

Example 5 Microbead Core-Dual Layer Tri-Extrusion Process

The core solution was prepared using a carrier agent of sunflower oilcombined with a pre-complexed Ganeden BC-30® probiotic active ingredient(Nozzle 1). The intermediate layer solution was prepared by heatingStearine-07 nutrient/stabilizing blend to 60° C. (Nozzle 2). The outerencapsulating layer was prepared by heating Carnuba Palm wax to 95° C.(Nozzle 3). The three solutions were then combined utilizingtri-extrusion on a customized Buchi Encapsulator B-390 to manufacturethe core-dual layered microbeads. The microbeads were collected andallowed to cool in a collection bath of ethanol.

The overall process was carried out at the following parameters

TABLE 7 Nozzle System Three Nozzle-Concentric-Outer Encapsulate 400 μm,Intermediate layer 300 μm, Core 200 μm Flow Rate 7 (Outer layer) 4(Intermediate layer), 2 (Core) Frequency 4500 Hz Pressure 0.5 Bar Amp 3Charge >1000 V

Example 6 Microbead Core-Sealing Layer Layer 3-D Printing Process

A core dispersion/filament was prepared using an active ingredient ofcaffeine. A filament of polylactic acid was utilized for the sealinglayer of the micro-bead. The two dispersions/filaments were then appliedlayer by layer using the 3-D system and software.

The overall process was carried out at the following parameters:

TABLE 8 3-D System Utilimaker 2 Sealing Filament Polylactic Acid (PLA),Flexible White, 3.0 mm Active Ingredient Caffeine Nozzle Temp 230degrees C. Speed 15 mm/sec Bed Temp 60 degrees C. Resolution 20 micron

Example 7 Pre-Microbead Core-Micronizing Process

A micronized microsphere core mass was manufactured by melting wax, thenadding an the active ingredient complex to the melted wax. This mass wasdried in a fluid bed until completely dry. The dry mass was thenmicronized utilizing a Fitz-Mill instrument. The final micronizedmicrospheres were added to polymers and sealing agents, and the mixtureswere then used in a rotary granulation system to produce microbeadswherein the active ingredient layers and sealing layers includemicrospheres.

The overall process was carried out at the following parameters:

TABLE 9 Rotary Granulator Freund Vector VFC 3 with a GXR-35 InsertMicronizing Fitz-Mill Active Ingredients Caffeine and Theanine

Microsphere inner particles were formed according to the method listedabove.

A binding solution containing 150 g of hydroxylpropyl methylcellulose(E5) was prepared.

The microspere inner particles were placed in the rotary granulator ofExample 1 equipped with a powder layering nozzle attachment. Bothnozzles positions were tangential.

The binding solution was sprayed through one nozzle concurrently with540 g of caffeine sprayed through the second nozzle under the followingparameters:

TABLE 10 Process Time minutes 0 15 30 45 60 75 90 105 120 135 DryingAirflow cfm — — — — — — — 50 50 50 Slit Air cfm 10 10 10 10 10 10 10 1010 10 Drying Accel — — — — — — — 95 95 95 Temp C. Product Temp C. 27 2727 27 27 27 27 27 32 50 Slit Air Temp C. 50 50 50 50 50 50 50 50 50 50Exhaust Temp C. 31 31 31 31 31 31 31 31 35 54 Rotor Speed rpm 300  300 300  300  300  300  300  300  300  300  Spray Rate g/min 10 10 10 10 2424 24 — — — Nozzle Pressure 10 10 10 10 10 10 10 — — — psi Powder Feed10 10 10 10 10 — — — — — g/min Eductor Air 14 14 14 14 14 — — — — —

Layering began shortly after the start of the spraying. Once the bindingsolution started to saturate the rotating microbead cores andinteracting with the caffeine and theanine powder, growth of the activeingredient layers on the core began.

Once all of the caffeine and theanine powder was consumed, the bindingsolution became a functional coating, essentially sealing the layeredmicrobeads.

Once all of the binding solution was consumed, drying air was activatedfor an additional 30 minutes until a product temperature of about 50° C.was achieved to dry the microbeads.

From the foregoing, it will be appreciated that specific embodiments ofthe invention have been described herein for purposes of illustration,but that various modifications may be made without deviating from thescope of the invention. Accordingly, the invention is not limited exceptas by the appended claims.

I claim:
 1. A non-prescription consumable product, comprising: a layeredmicrobead incorporated into the consumable product, the layeredmicrobead comprising: a microbead core comprising: a first bindingagent; and a plurality of first microspheres dispersed throughout thefirst binding agent, each first microsphere consisting of: a firstactive ingredient core consisting of a first active ingredient; and afirst polymer encapsulating the first active ingredient core; a firstactive ingredient layer encapsulating the microbead core, the firstactive ingredient layer comprising: a second active ingredient; a secondbinding agent; and a plurality of second microspheres dispersedthroughout the first active ingredient layer, wherein the second activeingredient is present in the first active ingredient layer outside ofthe plurality of second microspheres; and a second active ingredientlayer encapsulating the first active ingredient layer, the second activeingredient layer comprising: a third active ingredient; a third bindingagent; and a plurality of third microspheres dispersed throughout thesecond active ingredient layer; wherein the first active ingredient andthe second active ingredient are non-prescription active ingredients. 2.The non-prescription consumable product of claim 1, wherein each secondmicrosphere comprises: a second active ingredient core comprising afourth active ingredient; and a second polymer encapsulating the secondactive ingredient core.
 3. The non-prescription consumable product ofclaim 1, wherein the layered microbead has a diameter in the range offrom 25 to 5000 microns and each microsphere of the plurality of firstmicrospheres has a diameter in the range of from 0.5 to 100 microns. 4.The non-prescription consumable product of claim 1, wherein each of theplurality of second micro spheres has a diameter in the range of from0.5 to 100 microns.
 5. The non-prescription consumable product of claim1, wherein the first active ingredient is a different active ingredientfrom the second active ingredient.
 6. The non-prescription consumableproduct of claim 1, wherein the first active ingredient counteracts orreduces the effect of the second active ingredient.
 7. Thenon-prescription consumable product of claim 1, wherein the first activeingredient enhances or complements the effect of the second activeingredient.
 8. The non-prescription consumable product of claim 1,further comprising a sealing layer encapsulating the microbead core, thefirst active ingredient layer, and the second active ingredient layer.9. The non-prescription consumable product of claim 8, wherein thesealing layer comprises a material or combination of materials that donot substantially break down in a food or drinkable consumer beverageproduct.
 10. The non-prescription consumable product of claim 1, whereinthe amount of second binding agent in the first active ingredient layeris different from the amount of third binding agent in the second activeingredient layer.
 11. A non-prescription consumable product, comprising:a layered microbead incorporated into the consumable product, thelayered microbead comprising: a microbead core comprising: a firstbinding agent; and a plurality of first microspheres dispersedthroughout the first binding agent, each first microsphere consistingof: a first active ingredient core consisting of a first activeingredient; and a first polymer encapsulating the first activeingredient core; at least one active ingredient layer encapsulating themicrobead core, the active ingredient layer comprising: a second activeingredient; a second binding agent; and a plurality of secondmicrospheres dispersed throughout the at least one active ingredientlayer, wherein the second active ingredient is present in the at leastone active ingredient layer outside of the plurality of secondmicrospheres; and a first sealing layer disposed between the microbeadcore and the at least one active ingredient layer, wherein the firstsealing layer encapsulates the microbead core, the at least one activeingredient layer encapsulates the first sealing layer, and the firstsealing layer is free of active ingredients; wherein the first activeingredient and the second active ingredient are non-prescription activeingredients.
 12. The non-prescription consumable product recited inclaim 11, wherein the first sealing layer does not substantially breakdown prior to being consumed.
 13. The non-prescription consumableproduct recited in claim 11, wherein each second microsphere comprises:a second active ingredient core comprising a third active ingredient;and a second polymer encapsulating the second active ingredient core.14. The non-prescription consumable product recited in claim 11, whereinthe layered microbead has a diameter in the range of from 25 to 5000microns and each microsphere of the plurality of first microspheres hasa diameter in the range of from 0.5 to 100 microns.
 15. Thenon-prescription consumable product recited in claim 11, wherein each ofthe plurality of second microspheres has a diameter in the range of from0.5 to 100 microns.
 16. The non-prescription consumable product recitedin claim 11, wherein the first active ingredient is a different activeingredient from the second active ingredient.
 17. The non-prescriptionconsumable product recited in claim 11, wherein the first activeingredient counteracts or reduces the effect of the second activeingredient.
 18. The non-prescription consumable product recited in claim11, wherein the first active ingredient enhances or complements theeffect of the second active ingredient.
 19. The non-prescriptionconsumable product recited in claim 11, further comprising a secondsealing layer encapsulating the microbead core, the first sealing layer,and the at least one active ingredient layer.